In vitro metabolism of polychlorinated biphenyls and cytochrome P450 monooxygenase activities in dietary-exposed Greenland sledge dogs

Abstract

The in vitro metabolism of a polychlorinated biphenyl (PCB) mixture was examined using hepatic microsomes of dietary-exposed Greenland sledge dogs ( Canis familiaris) to an organohalogen-rich diet (Greenland minke whale blubber: EXP cohort) or a control diet (pork fat: CON cohort). The associations between in vitro PCB metabolism, activity of oxidative hepatic microsomal cytochrome P450 (CYP) isoenzymes and concentrations of PCBs and hydroxylated metabolites were investigated. The CON dogs exhibited a 2.3-fold higher depletion percentage for the PCB congeners having at least two pairs of vicinal meta-para Cl-unsubstituted carbons (PCB-18 and -33) relative to the EXP dogs. This depletion discrepancy suggests that there exist substrates in liver of the organohalogen-contaminated EXP dogs that can competitively bind and/or interfere with the active sites of CYP isoenzymes, leading to a lower metabolic efficiency for these PCBs. Testosterone (T) hydroxylase activity, determined via the formation of 6β-OH-T, 16α-OH-T, 16β-OH-T and androstenedione, was strongly correlated with the depletion percentages of PCB-18 and -33 in both cohorts. Based on documented hepatic microsomal CYP isoenzyme substrate specificities in canines, present associations suggest that primarily CYP2B/2C and CYP3A were inducible in sledge dogs and responsible for the in vitro metabolism of PCB-18 and -33.